MicroRNA-26b Enhances the Radiosensitivity of Hepatocellular Carcinoma Cells by Targeting EphA2

Abstract

Sensitizing hepatocellular carcinoma (HCC) cells to irradiation is important to achieve satisfactory therapeutic effect with low-dose radiotherapy. Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) is a member of the Eph receptor family that constitutes the largest family of tyrosine kinase receptors. EphA2 overexpression is one of the poor prognostic factors in many progressive cancers. Importantly, EphA2 is a potential target of microRNA-26b (miR-26b), and miR-26b expression is downregulated in several types of cancer. In this study, we measured the expression levels of miR-26b and EphA2 protein in seven human HCC cell lines by quantitative PCR and western blot analysis, respectively. Overall, lower miR-26b expression levels tended to be associated with higher EphA2 levels in HCC cell lines. Among the cell lines examined, 97H HCC cells expressed the lowest level of miR-26b and highest level of EphA2 protein. Thus, using 97H HCC cells, EphA2 mRNA was verified as the target of miR-26b by the luciferase reporter assay. Accordingly, a synthetic miR-26b, miR-26b mimics, was used to mimic the function of endogenous miR-26b. In 97H HCC cells transfected with miR-26b mimics or short-hairpin RNA targeting EphA2 mRNA, expression of EphA2 protein was reduced, which was associated with significantly lower proliferation rate and invasion ability and with higher apoptosis rate in response to low-dose irradiation, compared to control cells. In contrast, 97H HCC cells over-expressing EphA2 showed higher proliferation rate and invasion ability and lower apoptosis rate upon irradiation. These data suggest that miR-26b enhances the radiosensitivity of 97H HCC cells by targeting EphA2 protein.

MiR‐26b suppresses hepatocellular carcinoma development by negatively regulating ZNRD1 and Wnt/β‐catenin signaling

“…Studies demonstrated that miR‐26b could regulate HCC epithelial‐mesenchymal transition and metastasis through targeting USP9X and SMAD1 . Li et al reported that miR‐26b could inhibit HCC cell invasion and migration by directly binding to gene EphA2 . In addition, miR‐26b was reported to enhance the chemosensitivity of HCC cells by targeting TAK1 .…”

“…26,27 Li et al reported that miR-26b could inhibit HCC cell invasion and migration by directly binding to gene EphA2. 28 In addition, miR-26b was reported to enhance the chemosensitivity of HCC cells by targeting TAK1. 13 Thus, these findings suggest that miR-26b plays a crucial role in HCC as a tumor-suppressing miRNA.…”

MicroRNA‐26b suppresses tumorigenicity and promotes apoptosis in small cell lung cancer cells by targeting myeloid cell leukemia 1 protein

“…Recently, another miRNA family, miR‐26, is found to be profoundly involved in carcinogenesis, epithelial mesenchymal transition, and drug resistance in cancer cells [10–12]. MiR‐26b, a critical member of this family, is downregulated in multiple cancer cell lines and human carcinoma tissues [13–15]; while transfection with its mimic can inhibit proliferation and migration, decrease chemo‐resistance, and trigger apoptosis in various tumors, indicating the tumor suppressive effect of this miRNA [16–20]. Regarding lung cancer, a previous study confirmed that the expression of miR‐26b is downregulated in non‐small cell lung cancer (NSCLC) tissues, and may serve as a useful marker for the diagnosis and prognosis of NSCLC patients [14].…”

Radiosensitization of Hepatocellular Carcinoma through Targeting Radio-Associated MicroRNA

“…The expression profiles and the result of dual reporter assay revealed the interrelationship of miR-26b and EphA2. Transfection of miR-26b mimics or EphA2-shRNA leading to radiosensitization of 97H HCC cells and overexpression of EphA2 can protect 97H HCC cells from irradiation [79].…”